Ophthalmologic irrigation solutions and method

ABSTRACT

Solutions for perioperative intraocular application by continuous irrigation during ophthalmologic procedures are provided. These solutions include multiple agents that act to inhibit inflammation, inhibit pain, effect mydriasis (dilation of the pupil), and/or decrease intraocular pressure, wherein the multiple agents are selected to target multiple molecular targets to achieve multiple differing physiologic functions, and are included in dilute concentrations in a balanced salt solution carrier.

I. CROSS REFERENCE TO RELATED APPLICATIONS

The present invention is a continuation of currently pending U.S. patentapplication Ser. No. 13/420,440, filed Mar. 14, 2012, which is acontinuation of U.S. patent application Ser. No. 12/799,981 filed May 5,2010, now U.S. Pat. No. 8,173,707, which is a continuation of U.S.patent application Ser. No. 10/630,626 filed Jul. 30, 2003, nowabandoned, which claims the benefit of the filing date of U.S.Provisional Application No. 60/399,899, filed Jul. 30, 2002, priorityfrom the filing dates of which are hereby claimed under 35 U.S.C. §120.

II. FIELD OF THE INVENTION

The present invention relates to surgical irrigation solutions andmethods, and particularly to irrigation solutions for use duringophthalmologic procedures.

III. BACKGROUND OF THE INVENTION

Ophthalmologic surgery typically requires the use of a physiologicirrigation solution to protect and maintain the physiological integrityof intraocular tissues. Examples of ophthalmologic surgical proceduresusually requiring irrigation solutions are cataract operations, cornealtransplant operations, vitreoretinal operations and trabeculectomyoperations for glaucoma.

Solutions that have been used in ophthalmologic surgical irrigationinclude normal saline, lactated Ringer's solution and Hartmann'slactated Ringer's solution, but these are not optimal due to potentialunfavorable corneal and endothelial effects. Other aqueous solutionsthat include agents such as electrolytes, buffering agents for pHadjustment, glutathione and/or energy sources such as dextrose, betterprotect the tissues of the eye, but do not address other physiologicprocesses associated with surgery. One commonly used solution forophthalmologic irrigation is a two part buffered electrolyte andglutathione solution disclosed in U.S. Pat. No. 4,550,022 to Garabedianet al., the disclosure of which is hereby expressly incorporated byreference. The two parts of this solution are mixed just prior toadministration to ensure stability. These solutions are formulated witha goal of maintaining the health of ocular tissues during surgery.

Modifications of conventional aqueous irrigation solutions by theaddition of therapeutic agents have been proposed. For example, U.S.Pat. No. 5,523,316 to Gan et al. discloses the addition of one or moreagents for controlling intraocular pressure to irrigation solutions.Specific examples of agents for controlling intraocular pressuredisclosed in the Gan et al patent, all disclosure of which is herebyincorporated by reference, are beta-blockers (i.e., beta adrenergicreceptor antagonists) and alpha-2 adrenergic receptor agonists.Reference is also made to muscarinic agonists, carbonic anhydraseinhibitors, angiostatic steroids and prostaglandins as classes of drugsthat control intraocular pressure. Only agents intended for the controlof intraocular pressure are envisioned.

Another example of a modified solution is disclosed in International PCTApplication WO 94/08602 in the name of inventors Gan et al., thedisclosure of which is hereby incorporated by reference. Thisapplication discloses the inclusion of a mydriatic agent, such asepinephrine, in ocular irrigation solutions. Still another example isprovided by International PCT Application WO 95/16435 in the name ofinventors Cagle et al., which discloses the inclusion of non-steroidalanti-inflammatory drugs (NSAIDs) in an ophthalmologic irrigationsolution.

A topical ophthalmologic solution is disclosed in U.S. Pat. No.5,811,446 to Thomas that includes histidine, and which may include atleast one other active agent such as an anti-glaucoma agent, such astimolol or phenylephrine, a steroid or an NSAID. This reference teachesapplication of the composition to limit the inflammation associated withophthalmic procedures. The solution is administered by a dropper intothe cul-de-sac of the eye.

U.S. Pat. No. 5,624,893 to Yanni includes compositions including a woundhealing agent, such as a steroid or a growth factor, and/or a painmediator, such as an NSAID, a bradykinin antagonist, or a neurokinin-1antagonist. The compositions are intended for the treatment andprevention of corneal haze associated with laser irradiation andphotoablation.

Although many topically applied agents are available or have beenproposed to treat ocular inflammation, produce mydriasis (typicallynecessary to perform many types of ophthalmologic surgery), or tocontrol intraocular pressure, no previous attempt has been made tocombine these agents for use in a perioperative ocular irrigationsolution that is delivered in such a way so as to provide a constant,controlled delivery of multiple therapeutic agents, that act on multiplemolecular targets to address multiple physiologic functions, to thetissues of the eye throughout a procedure.

Various methods of ocular drug delivery are conventionally employed,each of which has limitations. These limitations may include corneal andconjuctival toxicity, tissue injury, globe perforation, optic nervetrauma, central retinal artery and/or vein occlusion, direct retinaldrug toxicity, and systemic side effects. For example, topicalmedications applied drop-wise are frequently impeded in reaching atargeted ocular site due to the eye's natural protective surface. Inmany situations, a rather small percentage of the medication applied tothe surface of the eye will actually reach the desired therapeutic siteof action.

One difficulty in ocular drug delivery during surgical procedures is toachieve the desired therapeutic concentration levels with the propertemporal control. The most desired pharmacokinetic effect is to be ableto rapidly achieve a therapeutic concentration range and subsequentlymaintain the drug concentration at a constant level. This is notachieved by conventional methods of ocular drug delivery. The challengeof achieving similar pharmacokinetic profiles is substantiallycompounded when it is desirable to simultaneously deliver more than onedrug. A unique group of factors affect the ability of a drug topenetrate the corneal epithelia, including the size of the molecule, itschemical structure and its solubility characteristics.

To achieve sufficient concentration of drug delivered to the back of theeye, drugs are frequently administered systemically at very high doses.These levels are necessary to overcome the blood-retina barrier thatprotects the back of the eye from selected drug molecules coming fromthe blood stream. For surgical procedures, injectable drug solutions aresometimes injected directly into the back of the eye. Subconjuctival andperibulbar periocular injections are used when higher localconcentrations are needed and when drugs with poor penetrationcharacteristics need to be delivered. Intracameral injections directlyinto the anterior chamber are used in cataract surgery. Whileintracameral injection provides a prompt method of achieving aconcentration, it can be associated with corneal toxicity. However, thismethod suffers from the fact that these drugs are quickly removed by theeye's natural circulatory process. Thus, injectable solutions rapidlylose their therapeutic benefit, often necessitating frequent, large doseinjections that can carry toxicity risks. Sustained releaseformulations, such as viscoelastic gels containing microcapsules, may beinjected intraocularly for a longer duration of action. However, theremay be some delay in reaching a local therapeutic concentration of drug.Hence, there exists a need for controlled methods of ocular deliveryduring ophthalmologic procedures.

IV. SUMMARY OF THE INVENTION

The present invention provides solutions for local ocular delivery ofmultiple active agents that act on a plurality of differing moleculartargets to perioperatively inhibit inflammation, inhibit pain, effectmydriasis (dilation of the pupil), and/or to decrease intraocularpressure. The solutions and methods of the present invention use atleast first and second therapeutic agents that are selected from thephysiologic functional classes of anti-inflammatory agents, analgesicagents, mydriatic agents and agents for decreasing intraocular pressure(“IOP reducing agents”), the second agent providing at least onephysiologic function different than a function or functions provided bythe first agent. The solutions are preferably applied by continuousirrigation of ocular tissues at the site of surgery during a majority ofthe operative procedure.

Solutions of this aspect of the present invention may include: (a) oneor more anti-inflammatory agents in combination with one or moreanalgesic agents, and optionally may also include one or more IOPreducing agents and/or mydriatic agents; (b) one or moreanti-inflammatory agents in combination with one or more IOP reducingagents, and optionally one or more analgesic and/or mydriatic agents;(c) one or more anti-inflammatory agents in combination with one or moremydriatic agents, and optionally one or more analgesic agents and/or IOPreducing agents; (d) one or more analgesic agents in combination withone or more IOP reducing agents, and optionally one or moreanti-inflammatory agents and/or mydriatic agents; (e) one or moreanalgesic agents in combination with one or more mydriatic agents, andoptionally one or more anti-inflammatory agents and/or IOP reducingagents; or (f) one or more mydriatic agents in combination with one ormore IOP reducing agents, and optionally one or more anti-inflammatoryand/or analgesic agents.

The present invention provides a solution constituting a mixture ofmultiple agents in low concentrations directed at inhibiting locally themediators of pain, inflammation, reducing intraocular pressure and/orcausing mydriasis, in a physiologic electrolyte carrier fluid. Theinvention also provides a method for perioperative delivery of theirrigation solution containing these agents directly to a surgical site,where it works locally at the receptor and enzyme levels to preemptivelylimit pain and inflammation, reduce intraocular pressure and/or causemydriasis, at the site. Due to the local perioperative delivery methodof the present invention, a desired therapeutic effect can be nearlyinstantaneously achieved with lower doses of agents than are necessarywhen employing systemic methods of delivery (e.g., intravenous,intramuscular, subcutaneous and oral) or by injection. When applied bycontinuous irrigation during a majority of the procedure, in accordancewith a preferred aspect of the invention, concentrations of agentsutilized may be lower than if the agents were applied drop-wise in asingle application or by intraocular injection.

The present invention has several advantages over other types ofcompositions and methods for delivery of active agents duringintraocular surgery. Liquid compositions for topical drop-wiseinstillation of a pharmaceutical agent to the eye do not always providean accurate method for delivering a defined dosage, because portions ofthe drop are either blinked away or drain away during administration.Furthermore, subsequent use of a normal irrigation solution can beanticipated to effectively dilute and remove a dose delivered drop-wisedelivered to the eye during an intraocular or topical ophthalmologicprocedure before the start of the surgical procedure, thereby reducingthe therapeutic efficacy of the agent.

In addition, the increased time over which the drugs can be delivered inaccordance with the present invention via irrigation during anintraocular or topical ophthalmologic procedure allows a lowerconcentration of the drugs to be used in the irrigation solution, whichreduces the risk of ocular toxicity. Due to pharmacokineticconsiderations, doses of agents delivered only pre-operatively willexhibit a variable concentration and efficacy as a function of time,reaching a peak of effectiveness some time after the initialapplication, then subsequently declining in efficacy due to aprogressively decreasing concentration. The particular pharmacokineticparameters after topical instillation of a drug will vary for each drugdepending on the solubility characteristics of the agent, the vehiclecomposition, and the pH, osmolality, tonicity and viscosity of theformulation. One advantage of the invention is that the irrigationsolutions provided maintain a constant concentration of active agents atthe ocular surgery site, thereby maintaining a constant therapeuticeffect.

The present invention provides for controlled, site-specific drugdelivery to the eye for the dual purposes of increasing efficacy anddecreasing side effects of ocular therapy. A therapeutic concentrationrange is rapidly achieved, and is subsequently maintained at aneffectively constant level during the period of irrigation.

The present invention also provides a method for manufacturing amedicament compounded as a dilute irrigation solution for use incontinuously irrigating an operative site or wound during an operativeprocedure. The method entails dissolving in a physiologic electrolytecarrier fluid a plurality of analgesic agents, anti-inflammatory agents,mydriatic agents, and/or agents that decrease intraocular pressure (“IOPreducing agents”), each agent included at a concentration of preferablyno more than 100,000 nanomolar, and more preferably no more than 10,000nanomolar, except for local anesthetics, which may be applied at aconcentration of no more than 100,000,000 nanomolar, preferably no morethan 10,000,000 nanomolar, more preferably no more than 1,000,000nanomolar, and still more preferably no more than 100,000 nanomolar.

The method of the present invention provides for the delivery of adilute combination of multiple receptor antagonists and agonists andenzyme inhibitors and activators directly to a wound or operative orprocedural site of the eye, during surgical, therapeutic or diagnosticprocedures for the inhibition of pain and inflammation, reduction orcontrol of intraocular pressure, and/or the promotion of mydriasis.Because the active ingredients in the solution are being locally applieddirectly to the ocular tissues in a continuous fashion during theprocedure, the drugs may be used efficaciously at extremely low dosesrelative to those doses required for therapeutic effect when the samedrugs are delivered systemically (e.g., orally, intramuscularly,subcutaneously or intravenously), or in a single application such asdrop-wise or by intraocular injection.

As used herein, the term “local” encompasses application of a drug inand around a wound or other operative or procedural site, and excludesoral, subcutaneous, intravenous and intramuscular administration. Asused herein throughout, the term “irrigation” is intended to mean theflushing of a wound or anatomic structure with a stream of liquid. Theterm “continuous” as used herein encompasses uninterrupted application,repeated application at frequent intervals at a frequency sufficient tosubstantially maintain a predetermined therapeutic local concentrationof the applied agents, and applications which are uninterrupted exceptfor brief cessations such as to permit the introduction of other drugsor procedural equipment or due to operative technique, such that asubstantially constant predetermined therapeutic local concentration ismaintained locally at the wound or operative site.

As used herein, the term “wound”, unless otherwise specified, isintended to include surgical wounds, operative/interventional sites andtraumatic wounds.

As used herein, the terms “operative” and “procedural”, unless otherwisespecified, are each intended to include surgical, therapeutic anddiagnostic procedures.

The irrigation solution including selected therapeutic agents is locallyand perioperatively applied to ocular tissues of the operative site,e.g., intraocularly for intraocular procedures and to the exterior ofthe eye for superficial procedures. As used herein, the term“perioperative” encompasses application intraprocedurally, pre- andintraprocedurally, intra- and postprocedurally, and pre-, intra- andpostprocedurally. Preferably, the solution is applied preprocedurallyand/or postprocedurally as well as intraprocedurally. The irrigationsolution is most preferably applied to the wound or surgical site priorto the initiation of the procedure, or before substantial tissue trauma,and continuously throughout the duration of the procedure, topreemptively block pain and inflammation, inhibit intraocular pressureincreases, and/or cause mydriasis. In a preferred aspect of theinvention, continuous irrigation is delivered throughout a substantialportion of the procedure, before and during the majority of operativetrauma, and/or during the period when mydriasis may be required and/orcontrol of intraocular pressure may be required.

The advantages of low dose application of agents by irrigation with themethods and solutions of the present invention are three-fold. Systemicside effects that often limit the usefulness of these agents areavoided. Additionally, the agents selected for particular applicationsin the solutions of the present invention are highly specific withregard to the mediators on which they work. This specificity ismaintained by the low dosages utilized. Finally, the cost of theseactive agents per operative procedure is low.

More particularly: (1) local administration guarantees a knownconcentration at the target site, regardless of interpatient variabilityin metabolism, blood flow, etc.; (2) because of the direct mode ofdelivery, a therapeutic concentration is obtained nearly instantaneouslyand, thus, improved dosage control is provided; and (3) localadministration of the active agents directly to a wound or operativesite also substantially reduces degradation of the agents throughextracellular processes, e.g., first- and second-pass metabolism, thatwould otherwise occur if the agents were given systemically (e.g.,orally, intravenously, subcutaneously or intramuscularly). This isparticularly true for those active agents that are peptides, which aremetabolized rapidly. Thus, local administration permits the use ofcompounds or agents which otherwise could not be employedtherapeutically. Local, continuous delivery to the wound or operativesite minimizes drug degradation or metabolism while also providing forthe continuous replacement of that portion of the agent that may bedegraded, to ensure that a local therapeutic concentration, sufficientto maintain receptor occupancy, is maintained throughout the duration ofthe operative procedure.

Local administration of the solution perioperatively throughout asurgical procedure in accordance with the present invention producespreemptive analgesic, anti-inflammatory and/or control of intraocularpressure effects (if an IOP reducing agent is used), while maintainingmydriasis (if a mydriatic agent is used). To maximize the preemptiveanti-inflammatory, analgesic (for certain applications), IOP reduction(for certain applications) and mydriatic (for certain applications)effects, the solutions of the present invention are most preferablyapplied pre-, intra- and postoperatively. By occupying the targetedreceptors or inactivating or activating targeted enzymes prior to theinitiation of significant operative trauma locally, the agents of thepresent solution modulate specific pathways to preemptively inhibit thetargeted pathologic processes. If inflammatory mediators and processesare preemptively inhibited in accordance with the present inventionbefore they can exert tissue damage, and the mediators of increases inintraocular pressure are likewise preemptively inhibited, the benefit ismore substantial than if given after these processes have beeninitiated.

The irrigation solutions of the present invention include combinationsof drugs, each solution acting on multiple receptors or enzymes. Thedrug agents are thus simultaneously effective against a combination ofpathologic processes, including pain and inflammation, and/or processesmediating increases in intraocular pressure. The action of these agentsis expected to be synergistic, in that the multiple receptor antagonistsand inhibitory agonists of the present invention provide adisproportionately increased efficacy in combination relative to theefficacy of the individual agents.

Used perioperatively, the solution should result in a clinicallysignificant decrease in operative site pain and inflammation relative tocurrently used irrigation fluids, thereby decreasing the patient'spostoperative analgesic requirement and, where appropriate, allowingearlier patient recovery. It is also expected that preemptivelycontrolling intraocular pressure should decrease the need to treatelevated intraocular procedure postoperatively.

V. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention provides irrigation solutions for perioperativelocal application to ocular tissues, including intraocular and topicalapplication, which include multiple agents that act to inhibitinflammation, inhibit pain, effect mydriasis (dilation of the pupil),and/or to decrease or control intraocular pressure, wherein the multipleagents are selected to act on multiple, differing molecular targets toachieve multiple differing physiologic functions. The irrigationsolutions of the present invention are dilute solutions of multiplepain/inflammation inhibitory agents, IOP reducing agents, and/ormydriatic agents in a physiologic liquid irrigation carrier. The carrieris suitably an aqueous solution that may include physiologicelectrolytes, such as normal saline or lactated Ringer's solution. Morepreferably, the carrier includes sufficient electrolytes to provide aphysiological balanced salt solution, a cellular energy source, abuffering agent and a free-radical scavenger.

A solution in accordance with the present invention can include (a) oneor more anti-inflammatory agents in combination with one or moreanalgesic agents, and optionally may also include one or more agentsthat act to reduce intraocular pressure (“IOP reducing agents”) and/ormydriatic agents; (b) one or more anti-inflammatory agents incombination with one or more IOP reducing agents, and optionally one ormore analgesic and/or mydriatic agents; (c) one or moreanti-inflammatory agents in combination with one or more mydriaticagents, and optionally one or more analgesic agents and/or IOP reducingagents; (d) one or more analgesic agents in combination with one or moreIOP reducing agents, and optionally one or more anti-inflammatory agentsand/or mydriatic agents; (e) one or more analgesic agents in combinationwith one or more mydriatic agents, and optionally one or moreanti-inflammatory agents and/or IOP reducing agents; or (f) one or moremydriatic agents in combination with one or more IOP reducing agents,and optionally one or more anti-inflammatory and/or analgesic agents.

Any of these solutions of the present invention may also include one ormore antibiotic agents. Suitable antibiotics for use in the presentinvention include ciprofloxacin, gentamicin, tobramycin and ofloxacin.Other antibiotics that are suitable for perioperative intraocular useare also encompassed by the present invention. Suitable concentrationsfor one antibiotic suitably included in the irrigation solutions of thepresent invention, ciprofloxacin, are 0.01 millimolar to 10 millimolar,preferably 0.05 millimolar to 3 millimolar, most preferably 0.1millimolar to 1 millimolar. Different antibiotics will be applied atdifferent concentrations, as may be readily determined.

In each of the surgical solutions of the present invention, the agentsare included in low concentrations and are delivered locally in lowdoses relative to concentrations and doses required with conventionalmethods of drug administration to achieve the desired therapeuticeffect. It is impossible to obtain an equivalent therapeutic effect bydelivering similarly dosed agents via systemic (e.g., intravenous,subcutaneous, intramuscular or oral) routes of drug administration sincedrugs given systemically are subject to first- and second-passmetabolism.

The concentration of each agent may be determined in part based on itsdissociation constant, K_(d). As used herein, the term “dissociationconstant” is intended to encompass both the equilibrium dissociationconstant for its respective agonist-receptor or antagonist-receptorinteraction and the equilibrium inhibitory constant for its respectiveactivator-enzyme or inhibitor-enzyme interaction. Each agent ispreferably included at a low concentration of 0.1 to 10,000 times K_(d),except for cyclooxygenase inhibitors, which may be required at largerconcentrations depending on the particular inhibitor selected.Preferably, each agent is included at a concentration of 1.0 to 1,000times K_(d) and most preferably at approximately 100 times K_(d). Theseconcentrations are adjusted as needed to account for dilution in theabsence of metabolic transformation at the local delivery site. Theexact agents selected for use in the solution, and the concentration ofthe agents, varies in accordance with the particular application.

The surgical solutions constitute a novel therapeutic approach bycombining multiple pharmacologic agents acting at distinct receptor andenzyme molecular targets. To date, pharmacologic strategies have focusedon the development of highly specific drugs that are selective forindividual receptor subtypes and enzyme isoforms that mediate responsesto individual signaling neurotransmitters and hormones. This standardpharmacologic strategy, although well accepted, is not optimal sincemany other agents simultaneously may be responsible for initiating andmaintaining a physiologic effect. Furthermore, despite inactivation of asingle receptor subtype or enzyme, activation of other receptor subtypesor enzymes and the resultant signal transmission often can trigger acascade effect. This explains the significant difficulty in employing asingle receptor-specific drug to block a pathophysiologic process inwhich multiple transmitters play a role. Therefore, targeting only aspecific individual receptor subtype is likely to be ineffective.

In contrast to the standard approach to pharmacologic therapy, thetherapeutic approach of the present surgical solutions is based on therationale that a combination of drugs acting simultaneously on distinctmolecular targets is required to inhibit the full spectrum of eventsthat underlie the development of a pathophysiologic state. Furthermore,instead of targeting a specific receptor subtype alone, the surgicalsolutions are composed of drugs that target common molecular mechanismsoperating in different cellular physiologic processes involved in thedevelopment of pain and inflammation, the reduction in intraocularpressure, and the promotion of mydriasis. In this way, the cascading ofadditional receptors and enzymes in the nociceptive, inflammatory, andintraocular-pressure-increasing pathways is minimized by the surgicalsolutions. In these pathophysiologic pathways, the surgical solutionscan inhibit the cascade effect both “upstream” and “downstream” (i.e.,both at points of divergence and convergence of pathophysiologicpathways).

Preferred solutions of the present invention for use duringophthalmologic surgical procedures include one or more anti-inflammatoryagents in combination with one or more mydriatic agents. Such preferredsolutions may also include one or more analgesic agents and/or one ormore IOP reducing agents, depending on whether a given procedure orcondition treated thereby is associated with a high incidence of pain orincreased intraocular procedure, respectively.

These agents are included at dilute concentrations in a physiologicaqueous carrier, such as any of the above-described carriers, e.g., abalanced salt solution. The solution may also include a viscosityincreasing agent, e.g., a biocompatible and biodegradable polymer, forlonger intraocular retention. The concentrations of the agents aredetermined in accordance with the teachings of the invention for direct,local application to ocular tissues during a surgical procedure.Application of the solution is carried out perioperatively, i.e.:intra-operatively; pre- and intra-operatively; intra- andpost-operatively; or pre-, intra- and post-operatively. The agents maybe provided in a stable one-part or two-part solution, or may beprovided in a lyophilized form to which a one-part or two-part carrierliquid is added prior to use.

Functional classes of ophthalmologic agents that would be advantageousfor use in perioperative ophthalmologic irrigation solutions of thepresent invention are now further described.

A. Anti-Inflammatory Agents

Preferred anti-inflammatory agents for use in the ophthalmologicsolutions of the present invention include topical steroids, topicalnon-steroidal anti-inflammatory drugs (NSAIDs) and specific classes ofanti-inflammatory agents that are suitably used intraocularly, such astopical anti-histamines, mast cell inhibitors and inhibitors ofinducible nitric oxide synthase (iNOS). Other anti-inflammatory agentsdescribed below as pain/inflammation inhibitory agents, and otheranti-inflammatory agents not disclosed herein, which are suitable forocular use, are also intended to be encompassed by the presentinvention.

Examples of steroids that are believed to be suitable for use in thepresent invention include dexamethasone, fluorometholone andprednisolone. Examples of NSAIDS that are believed to be suitableinclude flurbiprofen, suprofen, diclofenac, ketoprofen and ketorolac.Selection of an NSAID will depend in part on a determination thatexcessive bleeding will not result. Examples of anti-histamines that arebelieved to be suitable include levocabastine, emedastine andolopatadine. Examples of mast cell inhibitors that are believed to besuitable include cromolyn sodium, lodoxamide and nedocromil. Examples ofagents that act as both anti-histamine agents and mast cell inhibitors,and which are suitable for use in the present invention, includeketotifen and azelastine Inhibitors of iNOS that are believed to besuitable include N^(G)-monomethyl-L-arginine, 1400 W, diphenyleneiodium,S-methyl isothiourea, S-(aminoethyl) isothiourea,L-N⁶-(1-iminoethyl)lysine, 1,3-PBITU, and 2-ethyl-2-thiopseudourea.

B. Analgesic Agents

The term “analgesic agent” as used herein with reference toophthalmologic solutions and methods is intended to encompass bothagents that provide analgesia and agents that provide local anesthesia.Preferred analgesic agents for use in the ophthalmologic solutions ofthe present invention include topical local anesthetics and topicalopioids. Other analgesic agents described below as pain/inflammationinhibitory agents, and other analgesic agents not disclosed herein,which are suitable for ocular use, are also intended to be encompassedby the present invention.

Examples of local anesthetics that are believed to be suitable for usein the present invention include lidocaine, tetracaine, bupivacaine andproparacaine. Examples of opioids that are believed to be suitable foruse in the present invention include morphine, fentanyl andhydromorphone.

C. Mydriatic Agents

Preferred mydriatic agents for use in the ophthalmologic solutions ofthe present invention, to dilate the pupil during surgery, includesympathomimetics, including alpha-1 adrenergic receptor agonists, andanticholinergic agents, including anti-muscarinics. Anticholinergicagents may be selected when longer action is desired, because theyprovide both cycloplegia (paralysis of the ciliary muscle) andmydriasis, e.g., tropicamide exhibits a half-life of approximately 4-6hours. However, for many procedures, alpha-1 adrenergics will bepreferred because they provide mydriasis but not cycloplegia. Alpha-1adrenergics are thus shorter acting, causing mydriasis during a surgicalprocedure and allowing the pupil to return to its normal state shortlyafter completion of the procedure. Examples of suitable adrenergicreceptor agonists active at alpha-1 receptors include phenylephrine,epinephrine and oxymetazoline. Examples of suitable anticholinergicagents include tropicamide, cyclopentolate, atropine and homatropine.Other agents that cause mydriasis, and particularly short-actingmydriatic agents, are also intended to be encompassed by the presentinvention.

D. Agents that Decrease Intraocular Pressure

Preferred agents that decrease intraocular pressure for use in theophthalmologic solutions of the present invention include betaadrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha-2adrenergic receptor agonists and prostaglandin agonists. Examples ofsuitable beta adrenergic receptor antagonists are believed to includetimolol, metipranolol and levobunolol. Examples of suitable carbonicanhydrase inhibitors are believed to include brinzolamide anddorzolamide. Examples of suitable alpha-2 adrenergic receptor agonistsare believed to include apraclonidine, brimonidine and oxymetazoline.Other alpha-2 adrenergic receptor agonists suitable for ocular use anddescribed below as inflammatory/pain inhibitory agents may also suitablyfunction as IOP reducing agents within the solutions of the presentinvention. Suitable prostaglandin agonists are believed to includelatanoprost, travoprost and bimatoprost. When inflammation inhibition isa primary desired effect of the solution, and IOP control is needed, anIOP reducing agent other than a prostaglandin agonist may suitably beselected; to avoid the possibility that prostaglandin may enhancepost-surgical inflammation. Other agents that decrease intraocularpressure are also intended to be encompassed by the present invention.

E. Pain/Inflammation Inhibitory Agents

The following agents, referred to herein as pain/inflammation inhibitoryagents, may be suitable for use in the ophthalmologic solutions andmethods of the present invention as analgesic and/or anti-inflammatoryagents. The particular class(es) of agent, and individual agent(s)within a class, to be utilized for a particular ophthalmologicapplication can be readily determined by those of skill in the art inaccordance with the present invention.

For example, ocular inflammation models in the rabbit have been studiedby comparison of the inflammation response induced by the topicalapplication of several irritating agents, specifically carrageenan,Freund's adjuvant, alkali and croton oil. The methods involvemeasurement of the following parameters which can be determined afterthe application of each irritant to the eyes of female, white, NewZealand rabbits: corneal edema and the Tyndall effect (slitlampbiomicroscopy), corneal thickness (biometer-pachometer) and aqueoushumor levels of the prostaglandin E2 (R.I.A), total protein(Weichselbaum technique), albumin, albumin/globulin (Doumas technique)and leukocytes (coulter counter).

Validation studies have found that Croton oil 1-4% (40 μl) producededema and a Tyndall effect that showed a proportional increase withcroton oil concentration. Ultrasonic pachometer measurement of thevariation in corneal thickness (3-168 h) showed a dose-dependentresponse (p<0.01) from the 8th to the 168th hour. Uveitis andconsiderable increases in the levels of the prostaglandin E2 (4.50±0.40pg/0.1 ml vs. 260.03±2.03 pg/0.1 ml), total protein (0.25±0.05 g/l vs.2.10±0.08 g/l), albumin, albumin/globulin and leukocytes were observedin the aqueous humor 24 hours after topical application of croton oil 3%(40 μl). All the values obtained were statistically significant(p<0.01).

The topical application of 3% croton oil (40 μl) is most appropriate forthe evaluation of the inflammatory process in the anterior chamber andfor the determination of the effects of intraocular penetration. Theinflammatory mechanism in this model is thought to involve theactivation of the arachidonic acid pathway accompanied by the breakdownof the blood-aqueous barrier permitting high molecular weight proteinsto enter the aqueous humor.

The above models can be used to test the efficacy of drugs appliedtopically, such as by irrigation, in inhibiting inflammatory processesand effecting other ocular functions. A given agent or combination ofagents to be evaluated is applied to the eyes of rabbits after theapplication of each irritant to the eyes.

The solution may suitably include agents selected from the followingclasses of receptor antagonists and agonists and enzyme activators andinhibitors, each class acting through a differing molecular mechanism ofaction for pain and inflammation inhibition: (1) serotonin receptorantagonists; (2) serotonin receptor agonists; (3) histamine receptorantagonists; (4) bradykinin receptor antagonists; (5) kallikreininhibitors; (6) tachykinin receptor antagonists, including neurokinin₁and neurokinin₂ receptor subtype antagonists; (7) calcitoningene-related peptide (CGRP) receptor antagonists; (8) interleukinreceptor antagonists; (9) inhibitors of enzymes active in the syntheticpathway for arachidonic acid metabolites, including (a) phospholipaseinhibitors, including PLA₂ isoform inhibitors and PLC_(γ) isoforminhibitors, (b) cyclooxygenase inhibitors, and (c) lipoxygenaseinhibitors; (10) prostanoid receptor antagonists including eicosanoidEP-1 and EP-4 receptor subtype antagonists and thromboxane receptorsubtype antagonists; (11) leukotriene receptor antagonists includingleukotriene B₄ receptor subtype antagonists and leukotriene D₄ receptorsubtype antagonists; (12) opioid receptor agonists, including μ-opioid,δ-opioid, and κ-opioid receptor subtype agonists; (13) purinoceptoragonists and antagonists including P_(2X) receptor antagonists andP_(2Y) receptor agonists; (14) adenosine triphosphate (ATP)-sensitivepotassium channel openers; (15) local anesthetics; and (16) alpha-2adrenergic receptor agonists. Each of the above agents functions eitheras an anti-inflammatory agent and/or as an analgesic, i.e., anti-pain,agent. The selection of agents from these classes of compounds istailored for the particular application.

1. Serotonin Receptor Antagonists

Serotonin (5-HT) is thought to produce pain by stimulating serotonin₂(5-HT₂) and/or serotonin₃ (5-HT₃) receptors on nociceptive neurons inthe periphery. Most researchers agree that 5-HT₃ receptors on peripheralnociceptors mediate the immediate pain sensation produced by 5-HT. Inaddition to inhibiting 5-HT-induced pain, 5-HT₃ receptor antagonists, byinhibiting nociceptor activation, also may inhibit neurogenicinflammation. Activation of 5-HT₂ receptors also may play a role inperipheral pain and neurogenic inflammation. One goal of the solution ofthe present invention is to block pain and a multitude of inflammatoryprocesses. Thus, 5-HT₂ and 5-HT₃ receptor antagonists may both besuitably used, either individually or together, in the solution of thepresent invention. Amitriptyline (Elavil™) is believed to be apotentially suitable 5-HT₂ receptor antagonist for use in the presentinvention. Metoclopramide (Reglan™) is used clinically as an anti-emeticdrug, but displays moderate affinity for the 5-HT₃ receptor and caninhibit the actions of 5-HT at this receptor, possibly inhibiting thepain due to 5-HT release from platelets. Thus, it may also be suitablefor use in the present invention.

Other potentially suitable 5-HT₂ receptor antagonists includeimipramine, trazodone, desipramine, ketanserin. Other suitable 5-HT₃antagonists include cisapride and ondansetron. Therapeutic and preferredconcentrations for use of these drugs in the solution of the presentinvention are set forth in Table 1.

TABLE 1 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Concentrations ConcentrationsClass of Agent (Nanomolar) (Nanomolar) Serotonin₂ Receptor Antagonists:amitriptyline 0.1-1,000 50-500 imipramine 0.1-1,000 50-500 trazodone0.1-2,000 50-500 desipramine 0.1-1,000 50-500 ketanserin 0.1-1,00050-500 Serotonin₃ Receptor Antagonists: tropisetron 0.01-100   0.05-50  metoclopramide   10-10,000  200-2,000 cisapride 0.1-1,000 20-200ondansetron 0.1-1,000 20-200

2. Serotonin Receptor Agonists

5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptors are known to inhibitadenylate cyclase activity. Thus including a low dose of theseserotonin_(1A), serotonin_(1B) and serotonin_(1D) receptor agonists inthe solution should inhibit neurons mediating pain and inflammation. Thesame action is expected from serotonin_(1E) and serotonin_(1F) receptoragonists because these receptors also inhibit adenylate cyclase.

Buspirone is a potentially suitable 1A receptor agonist for use in thepresent invention. Sumatriptan is a potentially suitable 1A, 1B, 1D and1F receptor agonist. A potentially suitable 1B and 1D receptor agonistis dihydroergotamine. A suitable 1E receptor agonist is ergonovine.Therapeutic and preferred concentrations for these receptor agonists areprovided in Table 2.

TABLE 2 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Concentrations ConcentrationsClass of Agent (Nanomolar) (Nanomolar) Serotonin_(1A) Agonists:5-carboxyamidotryptamine 1-1,000 10-200 sumatriptan 1-1,000 10-200Serotonin_(1B) Agonists: CP93129 0.1-1,000   10-100 sumatriptan 1-1,00010-200 Serotonin_(1D) Agonists: naratriptan 0.1-1,000   10-100sumatriptan 1-1,000 10-200 Serotonin_(1E) Agonists: ergonovine 10-2,000  100-1,000 Serotonin_(1F) Agonists: sumatriptan 1-1,000 10-200

3. Histamine Receptor Antagonists

Histamine receptor antagonists may potentially be included in theirrigation solution. Promethazine (Phenergan™) is a commonly usedanti-emetic drug that potently blocks H₁ receptors, and is potentiallysuitable for use in the present invention. Other potentially suitable H₁receptor antagonists include terfenadine, diphenhydramine,amitriptyline, mepyramine and triprolidine. Because amitriptyline isalso effective as a serotonin₂ receptor antagonist, it has a dualfunction as used in the present invention. Suitable therapeutic andpreferred concentrations for each of these H₁ receptor antagonists areset forth in Table 3.

TABLE 3 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations Histamine₁ Receptor Antagonists: (Nanomolar) (Nanomolar)promethazine 0.1-1,000 50-200 diphenhydramine 0.1-1,000 50-200amitriptyline 0.1-1,000 50-500 terfenadine 0.1-1,000 50-500 mepyramine(pyrilamine) 0.1-1,000  5-200 tripolidine 0.01-100   5-20

4. Bradykinin Receptor Antagonists

Bradykinin receptors generally are divided into bradykinin₁ (B₁) andbradykinin₂ (B₂) subtypes. These drugs are peptides (small proteins),and thus they cannot be taken orally, because they would be digested.Antagonists to B₂ receptors block bradykinin-induced acute pain andinflammation. B₁ receptor antagonists inhibit pain in chronicinflammatory conditions. Depending on the application, the solution ofthe present invention may suitably include either or both bradykinin B₁and B₂ receptor antagonists. Potentially suitable bradykinin₁ receptorantagonists for use in the present invention include: the [des-Arg¹⁰]derivative of D-Arg-(Hyp³-Thi⁵-D-Tic⁷-Oic⁸)-BK (“the [des-Arg¹⁰]derivative of HOE 140”, available from Hoechst Pharmaceuticals); and[Leu⁸] des-Arg⁹-BK. Potentially suitable bradykinin₂ receptorantagonists include: [D-Phe⁷]-BK; D-Arg-(Hyp³-Thi^(5,8)-D-Phe⁷)-BK (“NPC349”); D-Arg-(Hyp³-D-Phe⁷)-BK (“NPC 567”); andD-Arg-(Hyp³-Thi⁵-D-Tic⁷-Oic⁸)-BK (“HOE 140”). Suitable therapeutic andpreferred concentrations are provided in Table 4.

TABLE 4 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Concentrations ConcentrationsClass of Agent (Nanomolar) (Nanomolar) Bradykinin₁ Receptor Antagonists:[Leu⁸] des-Arg⁹-BK 1-1,000 50-500 [des-Arg¹⁰] derivative of HOE 1401-1,000 50-500 [leu⁹] [des-Arg¹⁰] kalliden 0.1-500   10-200 Bradykinin₂Receptor Antagonists: [D-Phe⁷]-BK 100-10,000   200-5,000 NPC 349 1-1,00050-500 NPC 567 1-1,000 50-500 HOE 140 1-1,000 50-500

5. Kallikrein Inhibitors

The peptide bradykinin is an important mediator of pain andinflammation. Bradykinin is produced as a cleavage product by the actionof kallikrein on high molecular weight kininogens in plasma. Therefore,kallikrein inhibitors are believed to be therapeutic in inhibitingbradykinin production and resultant pain and inflammation. A potentiallysuitable kallikrein inhibitor for use in the present invention isaprotinin. Potentially suitable concentrations for use in the solutionsof the present invention are set forth below in Table 5.

TABLE 5 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations Kallikrein Inhibitor: (Nanomolar) (Nanomolar) aprotinin0.1-1,000 50-500

6. Tachykinin Receptor Antagonists

Tachykinins (TKs) are a family of structurally related peptides thatinclude substance P, neurokinin A (NKA) and neurokinin B (NKB). Neuronsare the major source of TKs in the periphery. An important generaleffect of TKs is neuronal stimulation, but other effects includeendothelium-dependent vasodilation, plasma protein extravasation, mastcell recruitment and degranulation and stimulation of inflammatorycells. Due to the above combination of physiological actions mediated byactivation of TK receptors, targeting of TK receptors is a reasonableapproach for the promotion of analgesia and the treatment of neurogenicinflammation.

a. Neurokinin₁ Receptor Subtype Antagonists

Substance P activates the neurokinin receptor subtype referred to asNK₁. A potentially suitable Substance P antagonist is([D-Pro⁹-[spiro-gamma-lactam]Leu¹⁰,Trp¹¹]physalaemin-(1-11)) (“GR82334”). Other potentially suitable antagonists for use in the presentinvention which act on the NK₁ receptor are:1-imino-2-(2-methoxy-phenyl)-ethyl)-7,7-diphenyl-4-perhydroisoindolone(3aR,7aR) (“RP 67580”); and2S,3S-cis-3-(2-methoxybenzylamino)-2-benzhydrylquinuclidine (“CP96,345”). Suitable concentrations for these agents are set forth inTable 6.

TABLE 6 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Class of Agent Therapeutic Preferred Neurokinin₁Receptor Concentrations Concentrations Subtype Antagonists (Nanomolar)(Nanomolar) GR 82334   1-1,000 10-500  CP 96,345   1-10,000 100-1,000 RP67580 0.1-1,000 100-1,000

b. Neurokinin₂ Receptor Subtype Antagonists

Neurokinin A is a peptide which is colocalized in sensory neurons withsubstance P and which also promotes inflammation and pain. Neurokinin Aactivates the specific neurokinin receptor referred to as NK₂. Examplesof potentially suitable NK₂ antagonists include:((S)—N-methyl-N-[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide(“(±)-SR 48968”); Met-Asp-Trp-Phe-Dap-Leu (“MEN 10,627”); andcyc(Gln-Trp-Phe-Gly-Leu-Met) (“L 659,877”). Suitable concentrations ofthese agents are provided in Table 7.

TABLE 7 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Class of Agent Therapeutic Preferred Neurokinin₂Receptor Subtype Concentrations Concentrations Antagonists: (Nanomolar)(Nanomolar) MEN 10,627  1-1,000  10-1,000 L 659,877 10-10,000 100-10,000(±)-SR 48968 10-10,000 100-10,000

7. CGRP Receptor Antagonists

Calcitonin gene-related peptide (CGRP) is a peptide which is alsocolocalized in sensory neurons with substance P, and which acts as avasodilator and potentiates the actions of substance P. An example of apotentially suitable CGRP receptor antagonist is I-CGRP-(8-37), atruncated version of CGRP. This polypeptide inhibits the activation ofCGRP receptors. Suitable concentrations for this agent are provided inTable 8.

TABLE 8 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations CGRP Receptor Antagonist: (Nanomolar) (Nanomolar)I-CGRP-(8-37) 1-1,000 10-500

8. Interleukin Receptor Antagonist

Interleukins are a family of peptides, classified as cytokines, producedby leukocytes and other cells in response to inflammatory mediators.Interleukins (IL) may be potent hyperalgesic agents peripherally. Anexample of a potentially suitable IL-1β receptor antagonist isLys-D-Pro-Thr, which is a truncated version of IL-1β. This tripeptideinhibits the activation of IL-1β receptors. Suitable concentrations forthis agent are provided in Table 9.

TABLE 9 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations Interleukin Receptor Antagonist: (Nanomolar) (Nanomolar)Lys-D-Pro-Thr 1-1,000 10-500

9 Inhibitors of Enzymes Active in the Synthetic Pathway for ArachidonicAcid Metabolites a. Phospholipase Inhibitors

The production of arachidonic acid by phospholipase A₂ (PLA₂) results ina cascade of reactions that produces numerous mediators of inflammation,known as eicosanoids. There are a number of stages throughout thispathway that can be inhibited, thereby decreasing the production ofthese inflammatory mediators. Examples of inhibition at these variousstages are given below.

Inhibition of the enzyme PLA₂ isoform inhibits the release ofarachidonic acid from cell membranes, and therefore inhibits theproduction of prostaglandins and leukotrienes resulting in decreasedinflammation and pain. An example of a potentially suitable PLA₂ isoforminhibitor is manoalide. Suitable concentrations for this agent areincluded in Table 10. Inhibition of the phospholipase C (PLC) isoformalso will result in decreased production of prostanoids and leukotrienesand, therefore, will result in decreased pain and inflammation. Anexample of a PLC isoform inhibitor is 1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione.

TABLE 10 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations PLA₂ Isoform Inhibitor: (Nanomolar) (Nanomolar) manoalide100-100,000 500-10,000

b. Cyclooxygenase Inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used asanti-inflammatory and analgesic agents. The molecular targets for thesedrugs are type I and type II cyclooxygenases (COX-1 and COX-2).Constitutive activity of COX-1 and induced activity of COX-2 both leadto synthesis of prostaglandins that contribute to pain and inflammation.

NSAIDs currently on the market (diclofenac, naproxen, indomethacin,ibuprofen, etc.) are generally nonselective inhibitors of both isoformsof COX, but may show greater selectively for COX-1 over COX-2, althoughthis ratio varies for the different compounds. Use of COX-1 and COX-2inhibitors to block formation of prostaglandins represents a bettertherapeutic strategy than attempting to block interactions of thenatural ligands with the seven described subtypes of prostanoidreceptors.

Potentially suitable cyclooxygenase inhibitors for use in the presentinvention are ketoprofen, ketorolac and indomethacin. Therapeutic andpreferred concentrations of these agents for use in the solution areprovided in Table 11. For some applications, it may also be suitable toutilize a COX-2 specific inhibitor (i.e., selective for COX-2 relativeto COX-1) as an anti-inflammatory/analgesic agent. Potentially suitableCOX-2 inhibitors include rofecoxib (MK 966), SC-58451, celecoxib(SC-58125), meloxicam, nimesulide, diclofenac, NS-398, L-745,337,RS57067, SC-57666 and flosulide.

TABLE 11 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations Cyclooxygenase Inhibitors: (Nanomolar) (Nanomolar)ketorolac 100-10,000 500-5,000 ketoprofen 100-10,000 500-5,000indomethacin 1,000-500,000  10,000-200,000 

c. Lipooxygenase Inhibitors

Inhibition of the enzyme lipooxygenase inhibits the production ofleukotrienes, such as leukotriene B₄, which is known to be an importantmediator of inflammation and pain. An example of a potentially suitable5-lipooxygenase antagonist is2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (“AA861”), suitable concentrations for which are listed in Table 12.

TABLE 12 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations Lipooxygenase Inhibitor: (Nanomolar) (Nanomolar) AA 861100-10,000 500-5,000

10. Prostanoid Receptor Antagonists

Specific prostanoids produced as metabolites of arachidonic acid mediatetheir inflammatory effects through activation of prostanoid receptors.Examples of classes of specific prostanoid antagonists are theeicosanoid EP-1 and EP-4 receptor subtype antagonists and thethromboxane receptor subtype antagonists. A potentially suitableprostaglandin E₂ receptor antagonist is8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-acetylhydrazide (“SC 19220”). A potentially suitable thromboxanereceptor subtype antagonist is[15-[1α,2β(5Z),3β,4α]-7-[3-[2-(phenylamino)-carbonyl]hydrazino]methyl]-7-oxobicyclo-[2,2,1]-hept-2-yl]-5-heptanoicacid (“SQ 29548”). Suitable concentrations for these agents are setforth in Table 13.

TABLE 13 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations Eicosanoid EP-1 Antagonist: (Nanomolar) (Nanomolar) SC19220 100-10,000 500-5,000

11. Leukotriene Receptor Antagonists

The leukotrienes (LTB₄, LTC₄, and LTD₄) are products of the5-lipooxygenase pathway of arachidonic acid metabolism that aregenerated enzymatically and have important biological properties.Leukotrienes are implicated in a number of pathological conditionsincluding inflammation. An example of a potentially suitable leukotrieneB₄ receptor antagonist is SC(+)-(S)-7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)-carbonyl]phenoxy(propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoicacid(“SC 53228”). Concentrations for this agent that are potentiallysuitable for the practice of the present invention are provided in Table14. Other potentially suitable leukotriene B₄ receptor antagonistsinclude[3-[-2(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino-3-oxopropyl)thio]methyl]thiopropanoicacid (“MK 0571”) and the drugs LY 66,071 and ICI 20,3219. MK 0571 alsoacts as a LTD₄ receptor subtype antagonist.

TABLE 14 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations Leukotriene B₄ Antagonist: (Nanomolar) (Nanomolar) SC53228 100-10,000 500-5,000

12. Opioid Receptor Agonists

Activation of opioid receptors results in anti-nociceptive effects and,therefore, agonists to these receptors are desirable. Opioid receptorsinclude the μ-, δ- and κ-opioid receptor subtypes. Examples ofpotentially suitable μ-opioid receptor agonists are fentanyl andTry-D-Ala-Gly-[N-MePhe]-NH(CH₂)—OH (“DAMGO”). An example of apotentially suitable δ-opioid receptor agonist is[D-Pen²,D-Pen⁵]enkephalin (“DPDPE”). An example of a potentiallysuitable κ-opioid receptor agonist is(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidnyl)cyclohexyl]-benzeneacetamide (“U50,488”). Suitable concentrations for each of these agentsare set forth in Table 15.

TABLE 15 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Concentrations ConcentrationsClass of Agent (Nanomolar) (Nanomolar) μ-Opioid Agonist: DAMGO 0.1-1000.5-20  sufentanyl 0.01-50   1-20 fentanyl 0.1-500  10-200 PL 0170.05-50  0.25-10  δ-Opioid Agonist: DPDPE 0.1-500 1.0-100 κ-OpioidAgonist: U50,488 0.1-500 1.0-100

13. Purinoceptor Antagonists and Agonists

Extracellular ATP acts as a signaling molecule through interactions withP₂ purinoceptors. One major class of purinoceptors are the P_(2X)purinoceptors which are ligand-gated ion channels possessing intrinsicion channels permeable to Na⁺, K⁺, and Ca²⁺. Potentially suitableantagonists of P_(2X)/ATP purinoceptors for use in the present inventioninclude, by way of example, suramin andpyridoxylphosphate-6-azophenyl-2,4-disulfonic acid (“PPADS”). Suitableconcentrations for these agents are provided in Table 16. Agonists ofthe P_(2Y) receptor, a G-protein coupled receptor, are known to effectsmooth muscle relaxation through elevation of inositol triphosphate(IP₃) levels with a subsequent increase in intracellular calcium. Anexample of a P_(2Y) receptor agonist is 2-me-S-ATP.

TABLE 16 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations Purinoceptor Antagonists: (Nanomolar) (Nanomolar) suramin100-100,000 10,000-100,000 PPADS 100-100,000 10,000-100,000

14. Adenosine Triphosphate (ATP)-Sensitive Potassium Channel Openers

Potentially suitable ATP-sensitive K⁺ channel openers for the practiceof the present invention include: (−)pinacidil; cromakalim; nicorandil;minoxidil;N-cyano-N′-[1,1-dimethyl-[2,2,3,3-³H]propyl]-N″-(3-pyridinyl)guanidine(“P 1075”); and N-cyano-N′-(2-nitroxyethyl)-3-pyridinecarboximidamidemonomethansulphonate (“KRN 2391”). Concentrations for these agents areset forth in Table 17.

TABLE 17 Therapeutic and Preferred Concentrations of Pain/InflammationInhibitory Agents Therapeutic Preferred Class of Agent ConcentrationsConcentrations ATP-Sensitive K⁺ Channel Opener: (Nanomolar) (Nanomolar)cromakalim 10-10,000 100-10,000 nicorandil 10-10,000 100-10,000minoxidil 10-10,000 100-10,000 P 1075 0.1-1,000   10-1,000 KRN 2391 1-10,000 100-1,000  (−)pinacidil  1-10,000 100-1,000 

15. Local Anesthetics

The solution of the present invention is preferably used for continuousinfusion throughout the surgical procedure to provide preemptiveinhibition of pain and inflammation. Local anesthetics (e.g., lidocaine,bupivacaine, etc.) are used clinically as analgesic agents and are knownto reversibly bind to sodium channels in the membrane of neuronal axons,thereby inhibiting axonal conduction and the transmission of painsignals from the periphery to the spinal cord. The local delivery ofextremely low or sub-clinical concentrations of lidocaine, a localanesthetic, has been shown to inhibit nerve injury discharge (Bisla Kand Tanalian D L, Concentration-dependent Effects of Lidocaine onCorneal Epithelial Wound Healing, Invest Ophthalmol Vis Sci 33(11), pp.3029-3033, 1992). Therefore, in addition to decreasing pain signals,local anesthetics, when delivered in extremely low concentrations, alsohave anti-inflammatory properties.

The inclusion of a local anesthetic in extremely low or “sub-anesthetic”concentrations in the irrigation solution provides a beneficialanti-inflammatory effect without exposing the patient to the systemictoxicity associated with currently used clinical doses of localanesthetics. Thus, in extremely low concentrations, a local anestheticis suitable for use in the present invention. Examples of representativelocal anesthetics useful in the practice of the present inventioninclude, without limitation, benzocaine, bupivacaine, chloroprocaine,cocaine, etiodocaine, lidocaine, mepivacaine, pramoxine, prilocaine,procaine, proparacaine, ropivacaine, tetracaine, dibucaine, QX-222,ZX-314, RAC-109, HS-37 and the pharmacologically active enantiomersthereof. Although not wishing to be bound by any particular theory, somelocal anesthetics are believed to act by inhibiting voltage-gated sodiumchannels. (See Guo, X. et al., “Comparative inhibition of voltage-gatedcation channels by local anesthetics,” Ann. N.Y. Acad. Sci. 625: 181-199(1991)). Particularly useful pharmacologically active enantiomers oflocal anesthetics include, for example, the R-enantiomer of bupivacaine.For purposes of the present invention, useful concentrations ofanesthetic agents delivered locally are generally in the range of about125 to about 100,000,000 nanomolar, more preferably about 1,000 to about10,000,000 nanomolar, and most preferably about 225,000 to about1,000,000 nanomolar. In one embodiment, the solutions of the inventioncomprise at least one local anesthetic agent delivered locally at aconcentration of no greater than 750,000 nanomolar. In otherembodiments, the solutions of the invention comprise at least one localanesthetic agent delivered locally at a concentration of no greater than500,000 nanomolar. Useful concentrations of representative specificlocal anesthetic agents are set forth below.

TABLE 18 Therapeutic and Preferred Concentrations of Specific LocalAnesthetic Agents Local Concentrations (Nanomolar) Anesthetics:Therapeutic Preferred More Preferred lidocaine 500-1,600,0004,000-1,200,000 900,000-1,100,000 bupivacaine 125-400,000 1,000-300,000225,000-275,000

16. Alpha-2 Adrenergic Receptor Agonists

All the individual nine receptors that comprise the adrenergic aminereceptor family belong to the G-protein linked superfamily of receptors.The classification of the adrenergic family into three distinctsubfamilies, namely α₁ (alpha-1), α₂ (alpha-2), and β (beta), is basedupon a wealth of binding, functional and second messenger studies. Eachadrenergic receptor subfamily is itself composed of three homologousreceptor subtypes that have been defined by cloning and pharmacologicalcharacterization of the recombinant receptors. Among adrenergicreceptors in different subfamilies (alpha-1 vs. alpha-2 vs. beta), aminoacid identities in the membrane spanning domain range from 36-73%.However, between members of the same subfamily (α_(1A) vs. α_(1B)) theidentity between membrane domains is usually 70-80%. Together, thesedistinct receptor subtypes mediate the effects of two physiologicalagonists, epinephrine and norepinephrine.

Distinct adrenergic receptor types couple to unique sets of G-proteinsand are thereby capable of activating different signal transductioneffectors. The classification of alpha-1, alpha-2, and beta subfamiliesnot only defines the receptors with regard to signal transductionmechanisms, but also accounts for their ability to differentiallyrecognize various natural and synthetic adrenergic amines. In thisregard, a number of selective ligands have been developed and utilizedto characterize the pharmacological properties of each of these receptortypes. Functional responses of alpha-1 receptors have been shown incertain systems to stimulate phosphatidylinositol turnover and promotethe release of intracellular calcium (via G_(q)), while stimulation ofalpha-2 receptors inhibits adenylyl cyclase (via G_(i)). In contrast,functional responses of beta receptors are coupled to increases inadenylyl cyclase activity and increases in intracellular calcium (viaG_(s)).

It is now accepted that there are three different alpha-1 receptorsubtypes which all exhibit a high affinity (subnanomolar) for theantagonist, prazosin. The subdivision of alpha-1 adrenoceptors intothree different subtypes, designated α_(1A), α_(1B), and α_(1D), hasbeen primarily based on extensive ligand binding studies of endogenousreceptors and cloned receptors. Pharmacological characterization of thecloned receptors led to revisions of the original classification suchthat the clone originally called the α_(1C) subtype corresponds to thepharmacologically defined α_(1A) receptor. Agonist occupation ofα_(1A-D) receptor subtypes results in activation of phospholipase C,stimulation of PI breakdown, generation of the IP₃ as second messengerand an increase in intracellular calcium.

Three different α₂-receptor subtypes have been cloned, sequenced, andexpressed in mammalian cells, referred to as α_(2A) (α₂-C10), α_(2B)(α₂-C2), α_(2C) (α₂-C4). These subtypes not only differ in their aminoacid composition but also in their pharmacological profiles anddistributions. An additional α₂-receptor subtype, α_(2D) (gene rg20),was originally proposed based on radioligand binding studies of rodenttissues but is now considered to represent a species homolog to thehuman α_(2A) receptor.

Functionally, the signal transduction pathways are similar for all threeα_(2A) receptor subtypes; each is negatively coupled to adenylatecyclase via G_(i/o). In addition, the α_(2A) and α_(2B) receptors havealso been reported to mediate activation of a G-protein coupledpotassium channel (receptor-operated) as well as inhibition of aG-protein associated calcium channel.

Pharmacologically, alpha-2 adrenergic receptors are defined as highlysensitive to the antagonists yohimbine (Ki=0.5-25 μM), atipamezole(Ki=0.5-2.5 μM), and idazoxan (Ki=21-35 μM) and with low sensitivity tothe alpha-1 receptor antagonist prazosin. Agonists selective for thealpha-2 adrenergic receptor class relative to the alpha-1 adrenergicreceptor class are UK14,304, BHT920 and BHT933. Oxymetazoline binds withhigh affinity and selectivity to the α_(2A)-receptor subtype (K_(D)=3μM), but in addition binds with high affinity to alpa-1 adrenergicreceptors and 5HT1 receptors. An additional complicating factor is thatalpha-2 adrenergic receptor ligands which are imidazolines (clonidine,idazoxan) and others (oxymetazoline and UK14304) also bind with highaffinity (nanomolar) to non-adrenoceptor imidazoline binding sites.Furthermore, species variation in the pharmacology of theα_(2A)-adrenoceptor exists. To date, subtype-selective alpha-2adrenergic receptor ligands show only minimal selectivity or arenonselective with respect to other specific receptors, such that thetherapeutic properties of subtype selective drugs are still underdevelopment.

A therapeutic field in which alpha-2 receptor agonists may be consideredto have potential use is as an adjunct to anesthesia, for the control ofpain and blockade of neurogenic inflammation. Sympathetic nervous systemstimulation releases norepinephrine after tissue injury, and thusinfluences nociceptor activity. Alpha-2 receptor agonists, such asclonidine, can inhibit norepinephrine release at terminal nerve fibreendings and thus may induce analgesia directly at peripheral sites(without actions on the CNS). The ability of primary afferent neurons torelease neurotransmitters from both their central and peripheral endingsenables them to exert a dual, sensory and “efferent” or “local effector”function. The term, neurogenic inflammation, is used to describe theefferent function of the sensory nerves that includes the release ofsensory neuropeptides that contribute, in a “feed-forward” manner, tothe inflammatory process. Agents that induce the release of sensoryneuropeptides from peripheral endings of sensory nerves, such ascapsaicin, produce pain, inflammation and increased vascularpermeability resulting in plasma extravasation. Drugs that block releaseof neuropeptides (substance P, CGRP) from sensory endings are predictedto possess analgesic and anti-inflammatory activity. This mechanism ofaction has been established for other drugs that exhibit analgesic andanti-inflammatory action in the periphery, such as sumatriptan andmorphine, which act on 5HT1 and μ-opioid receptors, respectively. Bothof these drugs are agonists that activate receptors that share a commonmechanism of signal transduction with the alpha-2 receptors. UK14304,like sumatriptan, has been shown to block plasma extravasation withinthe dura mater through a prejunctional action on alpha-2 receptors.

Evidence supporting a peripheral analgesic effect of clonidine wasobtained in a study of the effect of intra-articular injection of thedrug at the end of an arthroscopic knee surgery ((Gentili, M et al(1996) Pain 64: 593-596)). Clonidine is considered to exhibit nonopiateanti-nociceptive properties, which might allow its use as an alternativefor postoperative analgesia. In a study undertaken to evaluate theanalgesic effects of clonidine administered intravenously to patientsduring the postoperative period, clonidine was found to delay the onsetof pain and decrease the pain score. Thus, a number of studies havedemonstrated intra- and postoperative analgesia effects from drugsacting either at alpha-2 adrenergic receptors, indicating thesereceptors are good therapeutic targets for new drugs to treat pain.

From the molecular and cellular mechanism of action defined for alpha-2receptor agonists, such as UK14304, these compounds are expected toexhibit anti-nociceptive action on the peripheral terminals of primaryafferent nerves when applied intraoperatively in an irrigation solutiondirectly to tissues.

Alpha-2 receptor agonists are suitable for use in the current invention,delivered either as a single agent or in combination with otheranti-pain and/or anti-inflammatory drugs, to inhibit pain andinflammation. Representative alpha-2 receptor agonists for the practiceof the present invention include, for example: clonidine;dexmedetomidine; oxymetazoline;((R)-(−)-3′-(2-amino-1-hydroxyethyl)-4′-fluoro-methanesulfoanilide(NS-49); 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline(AGN-193080); AGN 191103 and AGN 192172, as described in Munk, S. etal., J. Med. Chem. 39: 3533-3538 (1996);5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14304);5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine(BHT920); 6-ethyl-5,6,7,8-tetrahydro-4H-oxaazolo[4,5-d]azepin-2-amine(BHT933), 5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphyl-imidazoline(A-54741).

TABLE 19 Therapeutic and Preferred Concentrations of Alpha-2 AdrenergicReceptor Agonists Therapeutic Therapeutic Most Acceptable EfficientPreferred Preferred Concentrations Concentrations ConcentrationsConcentration Compounds (nM) (nM) (nM) (nM) clonidine 0.002-200,0000.01-50,000  0.1-10,000 10-2,000 dexmedetomidine 0.002-200,0000.01-50,000  0.1-10,000 10-2,000 UK14304 0.002-200,000 0.01-50,000 0.1-10,000 10-2,000 oxymetazoline 0.001-100,000 0.01-25,000 0.05-15,000   5-10,000 NS-49 0.002-200,000 0.01-50,000  0.1-10,00010-2,000 AGN192172 0.005-100,000 0.1-25,000  1-5,000 10-1,000 AGN1930800.005-100,000 0.1-25,000  1-5,000 10-1,000 AGN191103 0.002-200,0000.1-25,000  1-5,000 10-1,000 A-54741 0.002-200,000 0.1-50,000   1-10,00010-2,000 BHT920 0.003-200,000 0.3-50,000   3-30,000 30-5,000 BHT9330.003-200,000 0.3-50,000   3-30,000 30-5,000

F. Multi-Function Agents

In a further aspect of the present invention, selection of preferredagents to include in an ophthalmologic irrigation solution takes intoconsideration particular agents that display efficacy in more than oneof the above functional classes. The previously described alpha-2adrenergic receptor agonists provide examples of this, as they mayfunction as both IOP reducing agents and agents that inhibitinflammation and pain. For example, oxymetazoline inhibits ocularinflammation by inhibiting release of sensory neurotransmitters (FuderH., J. Ocul. Pharmacol., 10:109-123 (1994)). Oxymetazoline alsofunctions as a mydriatic agent via agonist activity atalpha-1-adrenergic receptors and also decreases IOP via agonist activityat alpha-2-adrenergic receptors (Chu T. et al, Pharmacology, 53:259-270(1996)). NSAIDS, in addition to anti-inflammatory effects, also areindicated for inhibiting intra-operative miosis, thereby possessingmydriatic properties. Such multi-functional agents may suitably be usedin the ophthalmologic solutions of the present invention when combinedwith an additional agent or agents that provide at least one additionalophthalmologic function not already provided by the multifunctionalagent.

In addition to choosing multi-functional agents, avoiding toxicside-effects of these topically applied agents is also of importance. Anadvantage of topical delivery is a significant reduction in systemicside effects. However, local effects of these agents, such as reducedwound healing with high-concentration local anesthetics or steroids,must by considered. Therefore, local anesthetics at low concentrationsthat effectively inhibit neuronal discharge yet avoid wound-healingproblems are preferred for use in the present invention (Bisla K, et al,Invest. Ophthalmol. Vis. Sci., 33:3029-3033 (1992).). Because NSAIDShave been demonstrated to be as effective as steroids for controllinginflammation following ocular surgery (Dadeya S. et al, J. Pediatr.Ophthalmol. Strabismus., 39:166-168 (2002)), NSAIDS are preferred toavoid the potential non-specific detrimental effects of steroids.

Depending on the specific requirements of various ophthalmologicsurgical procedures, a variety of suitable irrigation solutions of thepresent invention including 2 or more agents may be formulated inaccordance with the present invention, but each solution might notinclude agents drawn from all of the named functional categories (i.e.,analgesic, anti-inflammatory, mydriati, and IOP reducing agents). Forexample, an irrigation solution formulated in accordance with thedisclosure herein for use during cataract surgery may not require ananalgesic, because this procedure is not as painful as a vitrectomy.

G. Irrigation Carriers

The active agents of the present invention are solubilized within aphysiologic liquid irrigation carrier. The carrier is suitably anaqueous solution that may include physiologic electrolytes, such asnormal saline or lactated Ringer's solution. More preferably, thecarrier includes one or more adjuvants, and preferably all of thefollowing adjuvants: sufficient electrolytes to provide a physiologicalbalanced salt solution; a cellular energy source; a buffering agent; anda free-radical scavenger. One suitable solution (referred to in theexamples below as a “preferred balanced salt solution” includes:electrolytes of from 50 to 500 millimolar sodium ions, from 0.1 to 50millimolar potassium ions, from 0.1 to 5 millimolar calcium ions, from0.1 to 5 millimolar magnesium ions, from 50 to 500 millimolar chlorideions, and from 0.1 to 10 millimolar phosphate; bicarbonate as a bufferat a concentration of from 10 to 50 millimolar; a cellular energy sourceselected from dextrose and glucose, at a concentration of from 1 to 25millimolar; and glutathione as a free-radical scavenger (i.e.,anti-oxidant) at a concentration of from 0.05 to 5 millimolar. The pH ofthe irrigation solution is suitable when controlled at between 5.5 and8.0, preferably at a pH of 7.4.

VI. METHOD OF APPLICATION

The solution of the present invention has applications for a variety ofoperative/interventional procedures, including surgical, diagnostic andtherapeutic techniques. The irrigation solution is appliedperioperatively during ophthalmologic surgery. As defined above, theterm “perioperative” encompasses application intraprocedurally, pre- andintraprocedurally, intra- and postprocedurally, and pre-, intra- andpostprocedurally. Preferably, the solution is applied preprocedurallyand/or postprocedurally as well as intraprocedurally. The irrigationsolution is most preferably applied to the wound or surgical site priorto the initiation of the procedure, preferably before substantial tissuetrauma, and continuously throughout a major portion or for the durationof the procedure, to preemptively block pain and inflammation, inhibitintraocular pressure increases, and/or cause mydriasis. As definedpreviously, continuous application of the irrigation fluid of thepresent invention may be carried out as an uninterrupted application, orrepeated and frequent irrigation of wounds or procedural sites at afrequency sufficient to maintain a predetermined therapeutic localconcentration of the applied agents, or an application in which theremay be intermittent cessation of irrigation fluid flow necessitated byoperating technique. At the conclusion of the procedure, additionalamounts of the therapeutic agents may be introduced, such as byintraocular injection of an additional amount of the irrigation fluidincluding the same or a higher concentration of the active agents, or byintraocular injection or topical application of the agents in aviscoelastic gel.

The concentrations listed for each of the agents within the solutions ofthe present invention are the concentrations of the agents deliveredlocally, in the absence of metabolic transformation, to the operativesite in order to achieve a predetermined level of effect at theoperative site. This solution utilizes extremely low doses of these painand inflammation inhibitors, due to the local application of the agentsdirectly to the operative site during the procedure.

In each of the surgical solutions of the present invention, the agentsare included in low concentrations and are delivered locally in lowdoses relative to concentrations and doses required with systemicmethods of drug administration to achieve the desired therapeutic effectat the procedural site.

VII. EXAMPLES

The following are exemplary formulations in accordance with the presentinvention suitable for ophthalmologic procedures.

Example 1

Exemplary ophthalmologic solutions of the present invention for useduring cataract removal surgery are described in Tables 20, 21 and 22.This solution, and the following solutions of Tables 23-25, are providedby way of example only, and are not intended to limit the invention.Anti-inflammatories are believed to be particularly useful in cataractsolutions of the invention, to potentially reduce the post-operativeincidence of, or hasten resolution of, cystoid macular edema (CME).These exemplary solutions and the other exemplary ophthalmologicirrigation solutions described herein below are provided in terms of theconcentration of each agent included in the previously describedpreferred balanced-salt solution. The solution may suitably be suppliedin 500 ml bags, this being the quantity of irrigation solution typicallyapplied during a procedure, by way of non-limiting example.

TABLE 20 Exemplary Cataract Solution Concentration (Nanomolar): Class ofMost Agent Drug Therapeutic Preferred Preferred anti- flurbiprofen10-1,000,000 100-100,000 1,000-10,000 inflam- matory IOP red. timolol10-1,000,000 100-100,000 1,000-10,000 agent mydriatic phenylephrine50-500,000   500-100,000 1,000-10,000

TABLE 21 Alternate Exemplary Cataract Solution Concentration(Nanomolar): Class of Most Agent Drug Therapeutic Preferred Preferredanti- ketoprofen 10-1,000,000 100-100,000 1,000-10,000 inflam- matoryIOP red. timolol 10-1,000,000 100-100,000 1,000-10,000 agent mydriatictropicamide 10-1,000,000 100-100,000 1,000-10,000

TABLE 22 Alternate Exemplary Cataract Solution Concentration(Nanomolar): Class of Most Agent Drug Therapeutic Preferred Preferredmydriatic, oxymetazoline 10-1,000,000 100-100,000 1,000-10,000 IOP red.agent anti- flurbiprofen 10-1,000,000 100-100,000 1,000-10,000inflammatory

Example 2

A similar irrigation solution including multiple agents for effectivereduction of inflammation and to provide mydriasis for invasiveophthalmologic surgery, such as a trabeculectomy, is provided in Table23.

TABLE 23 Exemplary Trabeculectomy Solution Concentration (Nanomolar):Class of Most Agent Drug Therapeutic Preferred Preferred anti-prednisolone 10-1,000,000 100-100,000 1,000-10,000 inflam- matory anti-flurbiprofen 10-1,000,000 100-100,000 1,000-10,000 inflam- matory IOPred. timolol 10-1,000,000 100-100,000 1,000-10,000 agent mydriaticphenylephrine 50-500,000   500-100,000 1,000-10,000

Example 3

Irrigation solutions suitably used for extensive ophthalmologic surgeryor posterior ocular chamber procedures, such as vitrectomy, provideincreased analgesia by the addition of a local anesthetic. Suchsolutions of the present invention including a local anesthetic areprovided in Tables 24 and 25.

TABLE 24 Exemplary Local Anesthetic Ophthalmologic SolutionConcentration (Nanomolar): Most Class of Agent Drug TherapeuticPreferred Preferred IOP red. agent timolol 10-1,000,000 100-100,0001,000-10,000 anti- flurbiprofen 10-1,000,000 100-100,000 1,000-10,000inflammatory mydriatic tropicamide 10-1,000,000 100-100,000 1,000-10,000analgesic lidocaine 1,000-100,000,000  10,000-10,000,000100,000-1,000,000

TABLE 25 Alternate Exemplary Local Anesthetic Ophthalmologic SolutionConcentration (Nanomolar): Most Class of Agent Drug TherapeuticPreferred Preferred IOP red. agent timolol 10-1,000,000 100-100,0001,000-10,000 anti- flurbiprofen 10-1,000,000 100-100,000 1,000-10,000inflammatory mydriatic tropicamide 10-1,000,000 100-100,000 1,000-10,000analgesic bupivacaine 125-400,000   1,000-300,000   225,000-275,000 

While the preferred embodiment of the invention has been illustrated anddescribed, it will be appreciated that various changes to the disclosedsolutions and methods can be made therein without departing from thespirit and scope of the invention. For example, alternate paininhibitors, inflammation inhibitors, IOP reducing agents and mydriaticagents may be discovered that may augment or replace the disclosedagents in accordance with the disclosure contained herein. It istherefore intended that the scope of Letters Patent granted hereon belimited only by the definitions of the appended claims.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A method of irrigationduring an intraocular ophthalmologic procedure, comprising irrigatingintraocular tissues during an intraocular ophthalmologic procedure witha solution including at least an anti-inflammatory agent and a mydriaticagent in a liquid irrigation carrier, wherein the anti-inflammatoryagent comprises ketorolac and the mydriatic agent comprisesphenylephrine and the agents are included in a therapeutically effectiveamount for the maintenance of mydriasis during the procedure and thereduction of postoperative pain when delivered intraocularly during theintraocular ophthalmologic procedure.
 2. The method of claim 1, whereinthe ketorolac is included in the solution at a concentration of no morethan 100,000 nanomolar and the phenylephrine is included in the solutionat a concentration of no more than 500,000 nanomolar.
 3. The method ofclaim 1, wherein each of the agents contributes to the maintenance ofintraoperative mydriasis by providing for mydriasis or inhibitingmiosis.
 4. The method of claim 1, wherein the solution further comprisesan analgesic agent selected from the group consisting of localanesthetics and opioids.
 5. The method of claim 4, wherein: the localanesthetic, if selected, is selected from the group consisting oflidocaine, tetracaine, bupivacaine, and proparacaine; and the opioid, ifselected, is selected from the group consisting of morphine, fentanyland hydromorphone.
 6. The method of claim 1, wherein the solutionfurther comprises an agent for decreasing intraocular pressure (“IOPreducing agent”) selected from the group consisting of beta adrenergicreceptor antagonists, carbonic anhydrase inhibitors, alpha-2 adrenergicreceptor agonists, and prostaglandin agonists.
 7. The method of claim 6,wherein: the beta adrenergic receptor antagonist, if selected, isselected from the group consisting of timolol, metipranolol andlevobunolol; the carbonic anhydrase inhibitor, if selected, is selectedfrom the group consisting of brinzolamide and dorzolamide; the alpha-2adrenergic receptor agonist, if selected, is selected from the groupconsisting of apraclonidine, brimonidine and oxymetazoline; and theprostaglandin agonist, if selected, is selected from the groupconsisting of latanoprost, travoprost and bimatoprost.
 8. The method ofclaim 1, wherein the solution is continuously applied to the intraoculartissues during the intraocular procedure.
 9. The method of claim 1,wherein the liquid irrigation carrier further comprises an adjuvantselected from electrolytes sufficient to provide a physiologicalbalanced salt solution, a cellular energy source, a buffering agent, afree-radical scavenger and mixtures thereof.
 10. The method of claim 9,wherein; the electrolytes, if selected, comprise from 50 to 500millimolar sodium ions, from 0.1 to 50 millimolar potassium ions, from0.1 to 5 millimolar calcium ions, from 0.1 to 5 millimolar magnesiumions, from 50 to 500 millimolar chloride ions, and from 0.1 to 10millimolar phosphate; the buffer, if selected, comprises bicarbonate ata concentration of from 10 to 50 millimolar; the cellular energy sourceif selected, is selected from dextrose and glucose and is present at aconcentration of from 1 to 25 millimolar; and the free-radicalscavenger, if selected, comprises glutathione at a concentration of from0.05 to 5 millimolar.
 11. The method of claim 1, wherein the liquidirrigation carrier further comprises electrolytes sufficient to providea physiological balanced salt solution, a cellular energy source, abuffering agent and a free-radical scavenger.
 12. The method of claim11, wherein: the electrolytes comprise from 50 to 500 millimolar sodiumions, from 0.1 to 50 millimolar potassium ions, from 0.1 to 5 millimolarcalcium ions, from 0.1 to 5 millimolar magnesium ions, from 50 to 500millimolar chloride ions, and from 0.1 to 10 millimolar phosphate; thebuffer comprises bicarbonate at a concentration of from 10 to 50millimolar; the cellular energy source is selected from dextrose andglucose and is present at a concentration of from 1 to 25 millimolar;and the free-radical scavenger comprises glutathione at a concentrationof from 0.05 to 5 millimolar.
 13. The method of claim 1, wherein the pHof the irrigation solution is between 5.5 and 8.0.